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Radboud Universiteit Nijmegen, 17 maart 2016, Promotor : Kaanders, J.H.A.M. Co-promotor : Span, P.N., Contains fulltext : 155622.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, BACKGROUND: Although diffuse intrinsic pontine glioma (DIPG) carries the worst prognosis of all pediatric brain tumors, studies on prognostic factors in DIPG are sparse. To control for confounding variables in DIPG studies, which generally include relatively small patient numbers, a survival prediction tool is needed. METHODS: A multicenter retrospective cohort study was performed in the Netherlands, the UK, and Germany with central review of clinical data and MRI scans of children with DIPG. Cox proportional hazards with backward regression was used to select prognostic variables (P < .05) to predict the accumulated 12-month risk of death. These predictors were transformed into a practical risk score. The model's performance was validated by bootstrapping techniques. RESULTS: A total of 316 patients were included. The median overall survival was 10 months. Multivariate Cox analysis yielded 5 prognostic variables of which the coefficients were included in the risk score. Age

Item does not contain fulltext, BACKGROUND: There is no international consensus on surveillance strategies for differentiated thyroid carcinoma (DTC) after radiotherapy for childhood cancer. Ultrasonography could allow for early detection of DTC, however, its value is yet unclear since the prognosis of DTC is excellent. We addressed the evidence for the question: 'is outcome of DTC influenced by tumor stage at diagnosis?'. METHODS: A multidisciplinary working group answered the sub-questions: 'is recurrence or mortality influenced by DTC stage at diagnosis? Does detection of DTC at an early stage contribute to a decline in adverse events of treatment?' The literature was systematically reviewed, and conclusions were drawn based on the level of evidence (A: high, B: moderate to low, C: very low). RESULTS: In children, level C evidence was found that detection of DTC at an early stage is associated with lower recurrence and mortality rates. No evidence was found that it influences morbidity rates. In adults, clear evidence was found that less advanced staged DTC is a favorable prognostic factor for recurrence (level B) and mortality (level A). Additionally, it was found that more extensive surgery increases the risk to develop transient hypoparathyroidism (level A) and that higher doses of radioiodine increases the risk to develop second primary malignancies (level B). CONCLUSION: Identification of DTC at an early stage is beneficial for children (very low level evidence) and adults (moderate to high level evidence), even considering that the overall outcome is excellent. These results are an important cornerstone for the development of guidelines for childhood cancer survivors at risk for DTC.

Item does not contain fulltext, BACKGROUND: Post-surgical radiotherapy (RT) in combination with chemotherapy is considered as standard of care for medulloblastoma in children. Chemotherapy has been introduced to improve survival and to reduce RT-induced adverse effects. Reduction of RT-induced adverse effects was achieved by deleting (craniospinal) RT in very young children and by diminishing the dose and field to the craniospinal axis and reducing the boost volume to the tumour bed in older children. OBJECTIVES: Primary objectives: 1. to determine the event-free survival/disease-free survival (EFS/DFS) and overall survival (OS) in children with medulloblastoma receiving chemotherapy as a part of their primary treatment, as compared with children not receiving chemotherapy as part of their primary treatment; 2. to determine EFS/DFS and OS in children with medulloblastoma receiving standard-dose RT without chemotherapy, as compared with children receiving reduced-dose RT with chemotherapy as their primary treatment.Secondary objectives: to determine possible adverse effects of chemotherapy and RT, including long-term adverse effects and effects on quality of life. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 7), MEDLINE/PubMed (1966 to August 2013) and EMBASE/Ovid (1980 to August 2013). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (August 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the above treatments in children (aged 0 to 21 years) with medulloblastoma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and risk of bias assessment. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Where possible, we pooled results. MAIN RESULTS: The search identified seven RCTs, including 1080 children, evaluating treatment including chemoth

Item does not contain fulltext, BACKGROUND AND PURPOSE: To quantify renal and diaphragmatic interfractional motion in order to estimate systematic and random errors, and to investigate the correlation between interfractional motion and patient-specific factors. MATERIAL AND METHODS: We used 527 retrospective abdominal-thoracic cone beam CT scans of 39 childhood cancer patients (<18years) to quantify renal motion relative to bony anatomy in the left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) directions, and diaphragmatic motion in the CC direction only. Interfractional motion was quantified by distributions of systematic and random errors in each direction (standard deviations Sigma and sigma, respectively). Also, correlation between organ motion and height was analyzed. RESULTS: Inter-patient organ motion varied widely, with the largest movements in the CC direction. Values of Sigma in LR, CC, and AP directions were 1.1, 3.8, 2.1mm for the right, and 1.3, 3.0, 1.5mm for the left kidney, respectively. The sigma in these three directions was 1.1, 3.1, 1.7mm for the right, and 1.2, 2.9, 2.1mm for the left kidney, respectively. For the diaphragm we estimated Sigma=5.2mm and sigma=4.0mm. No correlations were found between organ motion and height. CONCLUSIONS: The large inter-patient organ motion variations and the lack of correlation between motion and patient-related factors, suggest that individualized margin approaches might be required.

Contains fulltext : 152450.pdf (publisher's version ) (Open Access), BACKGROUND: To report on the acute toxicity in children with medulloblastoma undergoing intensity-modulated radiation therapy (IMRT) with daily intrafractionally modulated junctions. METHODS: Newly diagnosed patients, aged 3-21, with standard-risk (SR) or high-risk (HR) medulloblastoma were eligible. A dose of 23.4 or 36.0Gy in daily fractions of 1.8Gy was prescribed to the craniospinal axis, followed by a boost to the primary tumor bed (54 or 55.8Gy) and metastases (39.6-55.8Gy), when indicated. Weekly, an intravenous bolus of vincristine was combined for patients with SR medulloblastoma and patients participating in the COG-ACNS-0332 study. Common toxicity criteria (CTC, version 2.0) focusing on skin, alopecia, voice changes, conjunctivitis, anorexia, dysphagia, gastro-intestinal symptoms, headache, fatigue and hematological changes were scored weekly during radiotherapy. RESULTS: From 2010 to 2014, data from 15 consecutive patients (SR, n = 7; HR, n = 8) were collected. Within 72 h from onset of treatment, vomiting (66 %) and headache (46 %) occurred. During week 3 of treatment, a peak incidence in constipation (33 %) and abdominal pain/cramping (40 %) was observed, but only in the subgroup of patients (n = 9) receiving vincristine (constipation: 56 vs 0 %, P = .04; pain/cramping: 67 vs 0 %, P = .03). At week 6, 73 % of the patients developed faint erythema of the cranial skin with dry desquamation (40 %) or moist desquamation confined to the skin folds of the auricle (33 %). No reaction of the skin overlying the spinal target volume was observed. CONCLUSIONS: Headache at onset and gastro-intestinal toxicity, especially in patients receiving weekly vincristine, were the major complaints of patients with medulloblastoma undergoing craniospinal irradiation with IMRT.

1 april 2014, Item does not contain fulltext, PURPOSE: Retrospective studies indicate that larger tumour volume is a strong prognostic indicator for poor tumour control after (chemo)radiotherapy for laryngeal cancer. The impact of tumour volume on the outcome of patients treated within a prospective study comparing accelerated radiotherapy (AR)+/-carbogen breathing and nicotinamide (ARCON) was investigated. METHODS AND MATERIALS: Of 345 patients with cT2-4 laryngeal cancer, pre-treatment computed tomography (CT) scans of 270 patients were available for tumour volume calculation. Contouring of the primary tumour and involved lymph nodes was reviewed by one experienced head and neck radiation oncologist. Kaplan-Meier plots were used for analysis of outcome. RESULTS: Of 137 AR and 133 ARCON patients, 57 and 80 versus 56 and 77 patients had glottic and supraglottic tumours, respectively. A correlation between primary tumour volume and T-stage was observed (Rs=.51, P<.01). In both treatment arms no correlation was detected between the primary tumour volume and local control (LC), regional control (RC) and metastasis-free survival (MFS). A strong correlation between total nodal volume and N-stage was found (Rs=.93, P<.01). Both in the AR and ARCON groups total nodal volume was not associated with poorer RC rate. However, based on individual lymph node analyses, nodal control was in favour of ARCON, irrespective of volume (P<.01). CONCLUSION: Neither primary tumour volume, nor total nodal volume is a prognostic factor for patients with cT2-4 laryngeal cancer treated with accelerated radiotherapy+/-carbogen breathing and nicotinamide. Additional analyses based on individual nodal volumes demonstrate an excellent regional control rate and a significant benefit of ARCON.

Item does not contain fulltext, PURPOSE: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. EXPERIMENTAL DESIGN: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. RESULTS: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. CONCLUSION: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732). Clin Cancer Res; 20(5); 1345-54. (c)2014 AACR.

Item does not contain fulltext, BACKGROUND: Aggressive fibromatosis (AF) or desmoid tumor of the head and neck region is a rare, usually unresectable, benign soft tissue tumor with locally aggressive behavior. METHODS AND RESULTS: A 31-year-old woman presented with a progressive trismus, a swelling in the retromandibular area, as well as loss of sensibility of the maxillary and mandibular branch of the trigeminal nerve. MRI of the head and neck revealed an infiltrative mass involving the masticator, parapharyngeal, and prevertebral and paravertebral space on the left with intracranial extension through the orbital fissure. After the fifth biopsy, 15 months after presentation, the diagnosis of AF was made. The tumor was unresectable, so intensity-modulated radiotherapy was given with curative intent using a total dose of 60 Gy in 30 fractions of 2 Gy. After 16 months, she showed progressive disease, for which tamoxifen 40 mg twice daily was started with a good response for 2 years. After that, she started with sorafinib, on which she has stable disease now. CONCLUSION: The often long delay in proper diagnosis and the treatment challenges of a desmoid tumor are illustrated in this case. Furthermore, this article reviews the literature concerning AF, especially of the head and neck region. Head Neck, 2013.

Item does not contain fulltext, PURPOSE: Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival. METHODS AND MATERIALS: Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptoms for /=2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis. RESULTS: With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively. CONCLUSIONS: For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks.

Item does not contain fulltext, PURPOSE: To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer. PATIENTS AND METHODS: Patients with cT2-4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. RESULTS: From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity. CONCLUSION: Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment.

Item does not contain fulltext, PURPOSE: To report the acute toxicity profile and compliance from a randomized Phase III trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen and nicotinamide (ARCON) in laryngeal cancer. METHODS AND MATERIALS: From April 2001 to February 2008, 345 patients with cT2-4 squamous cell laryngeal cancer were randomized to AR (n = 174) and ARCON (n = 171). Acute toxicity was scored weekly until Week 8 and every 2-4 weeks thereafter. Compliance to carbogen and nicotinamide was reported. RESULTS: Between both treatment arms (AR vs. ARCON) no statistically significant difference was observed for incidence of acute skin reactions (moist desquamation: 56% vs. 58%, p = 0.80), acute mucosal reactions (confluent mucositis: 79% vs. 85%, p = 0.14), and symptoms related to acute mucositis (severe pain on swallowing: 53% vs. 58%, p = 0.37; nasogastric tube feeding: 28% vs. 28%, p = 0.98; narcotic medicines required: 58% vs. 58%, p = 0.97). There was a statistically significant difference in median duration of confluent mucositis in favor of AR (2.0 vs 3.0 weeks, p = 0.01). There was full compliance with carbogen breathing and nicotinamide in 86% and 80% of the patients, with discontinuation in 6% and 12%, respectively. Adjustment of antiemesis prophylaxis was needed in 42% of patients. CONCLUSION: With the exception of a slight increase in median duration of acute confluent mucositis, the present data reveal a similar acute toxicity profile between both regimens and a good compliance with ARCON for clinical stage T2-4 laryngeal cancers. Treatment outcome and late morbidity will determine the real therapeutic benefit.

Item does not contain fulltext, PURPOSE: To develop a treatment technique for craniospinal irradiation using intensity-modulated radiotherapy (IMRT) with improved dose homogeneity at the field junction(s), increased target volume conformity, and minimized dose to the organs at risk (OARs). METHODS AND MATERIALS: Five patients with high-risk medulloblastoma underwent CT simulation in supine position. For each patient, an IMRT plan with daily intrafractionally modulated junction(s) was generated, as well as a treatment plan based on conventional three-dimensional planning (3DCRT). A dose of 39.6 Gy in 22 daily fractions of 1.8 Gy was prescribed. Dose-volume parameters for target volumes and OARs were compared for the two techniques. RESULTS: The maximum dose with IMRT was <107% in all patients. V(<95) and V(>107) were <1 cm(3) for IMRT compared with 3-9 cm(3) for the craniospinal and 26-43 cm(3) for the spinal-spinal junction with 3DCRT. These observations corresponded with a lower homogeneity index and a higher conformity index for the spinal planning target volume with IMRT. IMRT provided considerable sparing of acute and late reacting tissues. V(75) for the esophagus, gastroesophageal junction, and intestine was 81%, 81%, and 22% with 3DCRT versus 5%, 0%, and 1% with IMRT, respectively. V(75) for the heart and thyroid was 42% and 32% vs. 0% with IMRT. CONCLUSION: IMRT with daily intrafractionally modulated junction results in a superior target coverage and junction homogeneity compared with 3DCRT. A significant dose reduction can be obtained for acute as well as late-reacting tissues.

Contains fulltext : 96065.pdf (publisher's version ) (Closed access), PURPOSE: To evaluate the long-term outcome and morbidity after intensified treatment for locally advanced head-and-neck cancer. METHODS AND MATERIALS: Between May 2003 and December 2007, 77 patients with Stage III to IV head-and-neck cancer were treated with curative intent. Treatment consisted of accelerated radiotherapy to a dose of 68 Gy and concurrent cisplatin. Long-term survivors were invited to a multidisciplinary outpatient clinic for a comprehensive assessment of late morbidity with special emphasis on dysphagia, including radiological evaluation of swallowing function in all patients. RESULTS: Compliance with the treatment protocol was high, with 87% of the patients receiving at least five cycles of cisplatin and all but 1 patient completing the radiotherapy as planned. The 5-year actuarial disease-free survival and overall survival rates were 40% and 47%, respectively. Locoregional recurrence-free survival at 5 years was 61%. The 5-year actuarial rates of overall late Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) Grade 3 and Grade 4 toxicity were 52% and 25% respectively. Radiologic evaluation after a median follow-up of 44 months demonstrated impaired swallowing in 57% of the patients, including 23% with silent aspiration. Subjective assessment using a systematic scoring system indicated normalcy of diet in only 15.6% of the patients. CONCLUSION: This regimen of accelerated radiotherapy with weekly cisplatin produced favorable tumor control rates and survival rates while compliance was high. However, comprehensive assessment by a multidisciplinary team of medical and paramedical specialists revealed significant long-term morbidity in the majority of the patients, with dysphagia being a major concern.

Item does not contain fulltext, Background F-18-fluoro-L-thymidine (FLT) has been shown to be a useful PET tracer in the evaluation of brain tumours in adults. No studies of this modality in children with brain tumours, however, have been published. Objective In this report three children with brain tumours are presented in which FLT-PET was used for different diagnostic purposes, in addition to imaging with MRI and F-18-fluorodeoxyglucose-PET. The first patient showed that FLT-PET could be helpful in differentiating between infection and malignancy. In the second patient FLT-PET was used for differentiating recurrent disease from radiotherapy effects. In the third patient, in which biopsy was not possible, FLT-PET was used for the characte Conclusion These patients show that FLT-PET might be a useful modality in different stages of the evaluation of primary brain tumours in children. However, further research to determine the clinical value, relative to MRI and fluorodeoxyglucose-PET, is required before routine implementation of FLT-PET. Nucl Med Commun 31: 482-487 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.